I. Field of the Invention
The present invention relates generally to the fields of biology, chemistry, and medicine. More particularly, it concerns compounds, compositions and methods for the treatment and prevention of diseases such as cancer and other proliferative diseases.
II. Description of Related Art
Neckers and coworkers reported that the DNA gyrase inhibitor, novobiocin, and related natural products bind the Hsp90 C-terminus nucleotide binding pocket with low affinity (IC50˜700 μM) (Marcu, et al., 2000). Subsequent modifications to novobiocin, including to the coumarin scaffold and the benzamide side chain, led to several compounds with increased inhibitory activity (Yu, et al., 2005; Burlison, et al., 2006; Zhao, et al., 2010; Zhao, et al., 2011; Zhao and Blagg, 2013). Improved activities were also observed for analogues possessing a 2-indole (Burlison, et al., 2008), 3-indole (Peterson and Blagg, 2010) or a 4-methoxyphenyl (Zhao, et al., 2011) side chain. Further development of new novobiocin compounds continues to be of interest because the biological activity profiles of these compounds vary, the wide variety of potential diseases and disorders that may be treated or prevented with these compounds, and manufacturing and supply-chain related considerations.